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Background:  The oncoprotein Tax from the Human T-cell Leukemia Virus type-1 is the major mediator of viral pathogenesis in infected individuals. Expression of Tax under the regulation of the granzyme B promoter in transgenic mice results in a lymphoproliferative disorder with features resembling adult T cell leukemia-lymphoma. Recent studies have shown that the transcription factor, nuclear factor kB (NF-kB), regulates critical survival pathways in a variety of cancers, including HTLV-1 transformed CD4 T cells. The activation of NF-kB is controlled by proteasome-mediated degradation of the inhibitor of nuclear factor kBa (IkBa). Tax transgenic tumors exhibit constitutive activation of NFkB and elevated expression levels of NFkB inducible cytokines, including IL-6, IL-10, IL-15, and IFN-g. Inhibitors of NFkB activation, sodium salicylate and cyclopentenone prostaglandins, blocked spontaneous proliferation of Tax transgenic mouse spleen cells. In addition, Tax-induced tumor cells, which are resistant to g-irradiation-induced apoptosis, became sensitive to apoptosis in the presence of sodium salicylate and prostaglandins. These results strongly suggest that Tax-mediated induction of NFkB activity contributes to tumorigenesis in vivo. Thus, this tumor system is an excellent animal model to assess the effects of NFkB inhibitors.

Methods:>  We investigated the effects of PS-341, a peptide boronate inhibitor of the proteasome in Tax transgenic tumors in vitro and in vivo.

Results:  In Tax transgenic mice, PS-341 administered thrice weekly inhibited tumor associated NFkB activity. Quantitation of proliferation, apoptosis and IL-6 secretion by tumor cells in culture revealed that the effects of PS-341 on cell growth largely correlated with inhibition of NFkB mediated pathways.

Conclusions:  However, the effect of PS-341 on the growth of tumors in Tax transgenic mice revealed heterogeneity in drug responsiveness.  Annexin V staining indicated that PS-341 response in vivo correlated with sensitivity to girradiation induced apoptosis. On the other hand, transplanted Tax tumors in Rag-1 mice showed consistent inhibition of tumor growth in response to the same drug regimen.

Keywords: HTLV-1 Tax; NFkB inhibitor; Tumorigenesis